The passage of Ca2+ in a selective manner across the lipid bilayer of the cellular plasma membrane occurs by way of several protein families, one of them being voltage-dependent calcium channels (VDCC). These channels are multi-protein assemblies that serve as “switchboards” for the highly regulated Ca2+ signal. They communicate with a large number of cellular players involved in amplifying, terminating or modulating this critical pathway.
Two classes of assemblies gate the flow of Ca2+ in response to the voltage state of the plasma membrane. The structurally related but distinct classes are sensitive to low (CaV3) or higher (CaV1 or 2) relative voltage shifts. CaV1 or 2 subfamilies couple excitation of the cell to a variety of processes, depending on cell type, including contraction, secretion and transcription. Furthermore, signal pathway crosstalk requires regulation of channel action by a small host of molecules. An example of such interactions is the GPCR signaling modulation of CaV2 channels. Association of liberated Gbg with the calcium channel as a result of GPCR activation has a notable effect on function, with Gbg behaving as an allosteric effector.
The VDCC (CaV1 or 2), as defined by biochemical purification of the stable complex, comprises four distinct polypeptides: α1, α2d, β and γ. α1 is the membrane pore forming subunit, which contains four transmembrane domains repeats, paralleling the tetrameric architecture of potassium channels. Each domain contains the canonical voltage-dependent ion channel organization i.e. six putative transmembrane segments. The membrane domains are connected by linkers located in the intracellular milieu, as are both the amino- and carboxy-termini. β, in contrast, is a soluble and intracellular protein. Four separate β genes have been catalogued, each with multiple splice variants. All four genes are expressed in the brain, while other tissues exhibit essential gene-specific expression, giving rise to embryonic lethality in β1 and β2 knockout mice. β3 and β4 knockouts or alleles lead to pathologies in a variety of physiological systems.
Since molecular cloning of β, much attention has been focused on its role in VDCC function. Two major directions emerged from these studies. First, β facilitates the proper localization or trafficking of the VDCC and the α1 subunit in particular to the cellular plasma membrane. Several different β isoforms chaperone the channel to its target. Second, β acts as an important modulator of the channel's electrophysiological properties. β alters activation and inactivation kinetics, causes a leftward shift in the I-V curve and, on the single channel level, induces an increase in the channel opening probability. Furthermore, the localization functionality has a marked impact on the electrophysiological aspect by increasing the number of channels at the membrane, significantly enhancing current amplitude.
The groundwork for understanding β's molecular mechanism was laid with the discovery that β bound α1 through a region in the linker between domain I and II, labeled the AID (for α1 interaction domain). Later studies have shown that β also interacts with other regions of α1, depending on the isoform, but the AID appears to be the primary, high affinity site of interaction. Notably, structure-function research has implicated the AID itself in playing a critical role in channel activity, especially in terms of its effects on current inactivation.
Examination of β's structure and functional correlates has been more limited. Sequence analysis of the various genes from differing species supported a division of the protein into two central conserved motifs flanked by diverging sequences. Though it is thought that these domains interact in a stable fashion, and represent a functional core of the full-length β protein, a framework for understanding β's function in the context of the VDCC and any other possible roles is as yet, lacking.